1-(2-aminophenyl)isoindolin-3-ones

ABSTRACT

DISCLOSED ARE ISOINDOLO(2,1-D)(1,4)BENZODIAZEPIN - 6 (7H)-ONES PHARMACEUTICALLY ACTIVE AND USEFUL AS SEDATIVES, SEDATIVE/HYPNOTICS, TRANQUILIZERS, ANTICONVULSANTS AND ANTIDEPRESSANTS. ALSO DISCLOSED ARE VARIOUS PROCESSES AND INTERMEDIATES INCLUDING THE COMPOUNDS WHICH ARE 1-(2AMINOPHENYL)ISOINDOLINES, 1-(2-AMINOPHENYL)ISOINDOLINE3-ONES, 2&#39;&#39;-AMINOBENZOPHENONE-2-CARBOXYLIC ACIDS, 2-(2AMINOBENZOIMIDOYL)BENZAMIDES AND 5 - METHYLMORPHANTHRIDIN-6(5H)-ONES.

United States Patent 3,558,648 1-(2-AMINOPHENYL)ISOINDOLIN-3-0NES GoetzE. Hardtmann, Florham Park, and Hans Ott, Convent Station, NJ.,assignors to Sandoz-Wander, Inc., a corporation of Delaware No Drawing.Application Jan. 3, 1966, Ser. No. 521,239, now Patent No. 3,475,449,dated Oct. 28, 19 69, which is a continuation-in-part of applicationSer. No. 463,378, June 11, 1965. Divided and this application July 2,1969, Ser. No. 857,250

Int. Cl. C07d 27/50 US. Cl. 260-325 7 Claims ABSTRACT OF THE DISCLOSUREDisclosed are isoindolo[2,1 d] [1,4] benzodiazepin 6- (7H)-onespharmaceutically active and useful as sedatives, sedative/hypnotics,tranquilizers, anticonvulsants and antidepressants. Also disclosed arevarious processes and intermediates including the compounds which are1-(2- aminophenyl) isoindolines, 1- (Z-aminophenyl) isoindoline- 3-ones,2'-aminobenzophenone-Z-carboxylic acids, 2-(2-aminobenzoimidoyl)benzamides and 5 methylmorphanthridin-6(5H)-ones.

This is a divisional application of copending application Ser. No.521,239, filed Ian. 3, 1966, now US. Patent No. 3,475,449, which in turnis a continuation-in-part of application Ser. No. 463,378, filed June11, 1965, now US.

Patent No. 3,375,246.

The subject invention is directed primarily to alternative processes forthe preparation of therapeutically active III Patented Jan. 26, 1971 andpharmaceutically acceptable isoindolobenzodiazepinones, particularlythose of the formula wherein one or both of rings A and B are eitherunsubstituted or substituted with one or more substituents, such as achlorine atom (-Cl), a fluorine atom (-F) and a bromine atom (-Br), inany of the available positions, but preferably at least one of thepositions 2-, l1- and 12; and R is either methyl or ethyl,

and to intermediates in said preparation.

Since compounds I have an asymmetric carbon atom C said compounds existas racemates, and as optically active enantiomers. Thisinventionincludes the racemates, the enantiomers and the method of producing themantiomers.

The object of this invention is to improve the procedure for obtainingcompounds I and their optically active enantiomers. In accomplishingthis object, a number of new compounds have been obtained asintermediates. Some of these intermediates, e.g. XI, XV and XVI, alsohave phar- 30 macological activity.

A schematic diagram of the steps leading to the preparation of racemiccompounds I and enantiomers thereof is presented in columns 2 and 3.Although said diagram illustrates the preparation of a preferredembodiment I, the

5 procedures are equally applicable to the preparation of all compoundsI.

II i IA 7 D E 11 o 0 H o I I It;

11 Y n 0 VIII 0 VII XIII 0 111, 0 on,

11 N u N XIV H CH3 N A on l 01 XII NHGH3 c1 or Anthraquinones H (with orwithout contemplated sub- N Hg NHCH3 XII mann Rearrangement.Alternatively, compound IV is prestituents on the benzene rings) areknown or are readily pared directly from the corresponding anthraquinoneII prepared according to well-established procedures. The reactionsleading from H to III to IV and from II directly to IV are alsowell-known and are not of the essence with respect to the instantinvention except insofar as they demonstrate how to obtain thosecompounds IV which by the Schmidt Reaction C.

If it is desired to introduce a chlorine atom into the 2-position ofcompound 1V (corresponding to the 2-position of compound I), compound 1V(unsubstituted in the 2 position) is dissolved either in glacial aceticacid or dimethylacetamide (DMA), and chlorine is introduced (reaction D)into the resulting solution to which iodine has been added. Only 5 partsby volume of DMA are respending morphanthridine-6,11(51-IJ-dione IV byBeckquired per part by weight of compound IV at C.,

whereas four times that volume of glacial acetic acid are needed at thesame reaction temperature.

The reaction can be effected at room temperature (20 C.) with relativelymore solvent or with boiling solvent.

Approximately three moles of chlorine per mole of IV are introduced intothe solution when reaction D is conducted at 100 0.; less is required atlower temperatures. Towards the end of the reaction the productprecipitates. If, after precipitation of compound VII, too much additional chlorine is introduced, a dichlorinated product is formed.Especially at lower temperatures, anhydrous potassium acetate may beadded to remove hydrochloric acid formed during the course of thereaction.

Compound VII is formed (with or without the indicated chlorine atom) bymelting together (reaction E) corresponding compounds VII and V.

Reaction F is effected by admixing compound VI'I with a melt ofanhydrous aluminum chloride and pulverized sodium chloride and heatingthe resultant at a temperature from 310 to 312 C. for about one hour.The procedure is a variation from that described in German Pat. No.551,256 of May 28, 1932. Materially increased yields are obtained whenanhydrous aluminum chloride is added to compound VII before the latteris introduced into the melt. Fluorine-containing compounds (VIII) arepreferably prepared by route E, F.

The reaction time can be varied between 30 minutes and 2 hours, butlittle variation is permissible with respect to the temperature.

Reaction G is efi'ected by adding a methanolic solution of sodiummethoxide and then, after evaporation of some solvent, adding methyliodide to a solution of compound V-IH (or IV). Suitable solvents forcompound VIII are anhydrous dimethylformamide, dimethylacetamide,dioxane and (under slightly different conditions) toluene. The solutionof sodium methoxide in methanol is, alternatively, replaced bycrystalline sodium methoxide, sodium hydride or sodium amide. Thereaction with methyl iodide takes from /2 to 24 hours. The reaction isover when the resulting mixture is approximately neutral. The reactionis conducted at temperatures from room temperature to about 50 C.

Compound IX (or one of its counterparts) is a key intermediate, as isthe corresponding compound X I. Although there are a number of ways forpreparing compound XI from the corresponding compound IX, the preferredprocedure includes reactions H and I.

Reaction H is effected with sodium in anhydrous liquid ammonia (sodiumamide being formed) in a pressure container at a temperature in therange of from 80 to 160 C. At least about 3 parts by volume of anhydrousliquid ammonia should be employed per part by weight of compound IX. Atleast one part by weight of sodium should be used per 45 parts by weightof compound IX when the reaction is carried out at from 110 to 120 C.The sodium may be replaced by an equivalent amount of either sodiumhydride, sodium amide or the corresponding derivatives of other alkalimetals. The reaction time is at least four hours at a temperature from110 to 120 C.

The product (compound X) of reaction H exists as tautomers X and X".

Reaction I is, e.g., a sodium borohydride reduction. Although thepreferred solvent is ethanol (containing at most 15 percent by volume ofwater), either methanol, propanol, methylene chloride/methanol,dioxane/water, glyme or diglyme/water can alternatively be used.Theoretically, only a molar equivalent of sodium borohydride isrequired, but an excess is indicated. The reaction time varies from 1 tohours at temperatures from 25 to 100 C.

Reaction I is also a reduction with, e.g., sodium borohydride. In lieuof the preferred 95% ethanol, either methanol, dioxane, glyme or glymecontaining up to percent by volume of water is employed as the solvent.Moreover, a solvent system additionally containing such cosolvents asbenzene, toluene and diethylether may be used. The volume of solvent issufficient to produce a clear solution of compound IX. At least oneequivalent of sodium borohydride is required but an excess is indicated.The reaction can be eifected in as little as 10 minutes under refluxconditions, but longer durations, e.g. overnight (about 17 hours), arerequired at room temperatures.

rReaction K may be accomplished with, e.g., thionyl chloride underreflux conditions. A considerable excess of thionyl chloride isindicated. Alternative procedures, such as (l) thionyl chloride in anorganic solvent like benzene 0r toluene at reflux for several hours and(2) phosphorus trior pentachloride in either chloroform or methylenechloride at a temperature between 20 to 60 C. produce the same compoundXIV.

Compound XIV is autoclaved (reaction L) in anhydrous liquid ammonia forfrom 5 to 25 hours at a temperature from 65 to 150 C. to obtain thecorresponding compound XI.

Reaction M is effected with anhydrous hydrazine under reflux conditions.

Reaction N is effected by adding sodium nitrite to an acid suspension ofcompound XV.

Reaction '0 is a saponification of an amide with 2 N (aq.) sodiumhydroxide (or alkali hydroxide solution of other concentrations) ofcompound IX, followed by neutralization with aqueous hydrochloric acid.Since compounds IX are insoluble in aqueous media, the saponification iscomplete as soon as a clear solution in sodium hydroxide is formed.Lower temperatures can be employed, and co-solvents such astetrahydrofurane, dioxane and lower alcohols may be used.

Ring closure P is effected according to the procedure of Dutch PatentNo. 20,363 of October 1964. An ethanolic solution of compound XII issaturated with ammonia prior to hydrogenation for from 3 to 60 hourswith Raney- Nickel catalyst at a temperature from about to about 150 C.and a pressure of about 2200 p.s.i.g. From 4 to 40 parts by volume ofabsolute ethanol are used per part by weight of compound XII. 'From 1 to6 parts by weight of Raney-Nickel catalyst are employed per 12 parts byweight of compound XII.

Reaction Q is an electrolytic reduction.

Reaction R is effected in an ethanolic solution (as least parts byvolume of ethanol per 15 parts by weight of compound XVI) with atertiary amine, e.g. tn'ethylamine, and either ethyl bromoorchloroacetate under reflux. .At least one equivalent of tertiary amineand from one to 4 equivalents of haloacetate are used per one equivalentof compound XVI. Either methanol or benzene can replace the ethanol.

Ring closure 8 is effected in boiling glacial acetic acid (at least 100parts by volume per 15 parts by weight of compound XVI used for reaction'R) Compounds I and their pharmaceutically acceptable acid additionsalts are useful as sedatives, sedative/hypnotics, tranquilizers,anticonvulsants and antidepressants. They are administered either orallyor parenterally in standard dosage forms, e.g. tablets and capsules, indaily doses of from 30 to 200 milligrams.

Each of the pharmaceutically active compounds of this invention may be,e.g. incorporated, for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 3percent binder, e.g. tragacanth; from 3 to 10 percent disintegratingagent, e.g. corn starch; from- 2 to 10 percent lubricant, e.g. talcum;from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an averagedosage of active ingredient; and q.s. 100 percent of filler, e.g.lactose; all percentages being by weight. Tablets are prepared accordingto standard tableting techniques, which are well-known in the art,employing the necessary amounts of conventional granulating liquids,e.g. alcohol SD30 and purified water. An exemplary tableting formulationfor the instant active compounds is:

Parts Title compound of Example 15 50 Tragacanth 2 Lactose 39.5 Cornstarch 5 Talcum 3 Magnesium stearate 0.5 Alcohol SD-30, Purified water,q.s.

The following examples illustrate the invention, all temperatures beingin degrees centigrade, parts and percentages being by weight unlessotherwise specified and the re lationship between parts by Weight andparts by volume being the same as that between the kilogram and theliter.

EXAMPLE 1 2-chloromorphanthridine-6,l 1 (5 H) -dione Dissolve 100 partsof morphanthridine-6,11(5H)-dione in 2000 parts by volume of hot glacialacetic acid. Add to the obtained solution a few iodine crystals and thenintroduce chlorine gas thereinto until the thus-produced reactionsolution (maintained at 100) becomes porridge-like from precipitatedreaction product. Cool the resultant to room temperature. Filter off thecrystals; wash them with water, ethanol and diethylether; and dry themat 100 in vacuo to obtain the title compound, melting point (M.P.) 295to 298.

EXAMPLE 2 2-chloromorphanthridine-6,11 (5 H) -dione Mix 16 parts ofanhydrous aluminum chloride and 4 parts of pulverized sodium chloride,and heat the obtained mixture to 305. Add to the thus-obtained melt(over a period of 5 minutes) a mixture of 4 parts ofN-p-chlorophenylphthalimide (prepared by melting togetherp-chloroaniline and phthalic anhydride) and 4 parts of anhydrousaluminum chloride. Heat the resultant for one hour at 310 to 312, cool,add thereto 125 parts of ice, shake the thus-obtained mixture and filteroff the produced precipitate. Dry the precipitate prior to dissolving itin chloroform. Extract the obtained chloroform solution with sodiumcarbonate (aq.) solution and then with water. Dry the resultingchloroform phase over sodium sulfate; admix the dried chloroform phasewith charcoal; filter off the charcoal; and evaporate the filtrate untilcrystallization of the title compound, M.P. 291 to 294, starts.

Dissolve 50 parts of 2-chloromorphanthridine-6,11(5H) dione (titlecompound of Example 1) in 500 parts by volume of anhydrousdimethylformamide (DMF). Add to the thus-obtained solution a solution of5.5 parts of sodium dissolved in 50 parts by volume of methanol. Fromthe resultant distill the solvent mixture off in vacuo until the volumeis approximately 125 parts (by volume).

At approximately 40 add to the obtained concentrate 75 parts of methyliodide and shake the resultant for several hours. Dilute the obtainedmaterial with 800 parts by volume of water, stir for one hour and thenfilter off precipitated crystals. Wash the crystals with water; dry thewashed crystals: dissolve the dried crystals in a minimal volume ofboiling ethanol; cool the thus-obtained ethanolic solution to roomtemperature and filter off the precipitated crystals of the titlecompound, M.P. 140 to 142. Recrystallize several times from ethanol toobtain title compound, M.P. 148 to 151.

Replacing the methyl iodide with an equivalent of dimethylsulfateresults in the preparation, in similar manner, of the title compound.Replacing the methyl iodide with an equivalent of ethyl iodide resultsin the preparation, in similar manner, of2-chloro-5-ethylmorphanthridine-6,11(5H)-dione, M.P. 135 to 137.

EXAMPLE 4 l-amino-1-(S-chloro-Z-methyIaminophenyl)isoindolin- 3-one i ifNHg l l N. LNH 2 N11 -1y11 01 (I311?) 01 CH3 Dissolve 22 parts of2-chloro-5-methylmorphanthridine- 6,11(5H)-dione (title compound ofExample 3) in 150 parts by volume of anhydrous liquid ammonia. Add tothe thus-obtained solution a solution of 1.5 parts of sodium in 10 partsby volume of anhydrous liquid ammonia, and heat the resulting mixture ina pressure tube for 16 hours at 110 to 120. Cool the thus-producedreaction mixture to room temperature, and evaporate ammonia therefrom.(Dissolve the obtained crystalline residue in 250 parts by volume of 95%ethanol to prepare one of the starting materials for Example 5.)

Dissolve the obtained crystalline residue in chloroform, water-Wash theobtained chloroform solution (2 or 3 washings), dry the thus-washedsolution-and evaporate the chloroform therefrom in vacuo. Recrystallizethe obtained residue from diethylether to obtain the title compound aswhite crystals which start to decompose at Replacing the2-chloro-5-methylmorphanthridine-6,11 (5H)-dione with an equivalent ofS-methylmorphanthridine-6,11(5H)-dione results in the preparation, insimilar manner, of l-amino-1-(Z-methylaminophenyl)isoindolin- 3-one.

EXAMPLE 5 6O 1- (S-chloro-Z-methylaminophenyl) isoindolin-3 -one Add asolution of 10 parts of sodium borohydride to 250 parts by volume of theethanolic solution (see Example 4) ofl-amino-1-(5-chloro-2-methylaminophenyl) isoindolin-S-one, and refluxthe resulting mixture for. four hours. Cool the thus-refluxed materialto room temperature, and destroy any excessive sodium borohydride byadding 2 N hydrochloric acid slowly to said material. Thereafter,evaporate the ethanol therefrom and admix 2 N sodium hydroxide (aq.)solution with the residue until the pH thereof is in the range of from 8to 9.

Add ethylacetate to the resultant to facilitate crystallization. Filterotf formed precipitate. Extract aqueous phase of filtrate 3 times with200 parts (each) by volume of ethylacetate. Wash the combined organicphase with saturated (aq.) sodium chloride solution, dry the washedorganic phase and then concentrate same to 100 parts by volume. Collectthe precipitated crystals, combine same with previously-obtainedprecipitate and recrystallize from chloroform/ethanol to obtain titlecompound, M.P. 227 to 229.

Replacing the title compound of Example 4 with an equivalent of1-amino-1-(Z-methylaminophenyl)isoindo- 1in-3-one results in thepreparation, in similar manner, of1-(2-methylaminophenyl)isoindolin-3-one, M.P. 194 to 196, thehydrochloride of which has a melting point of from 215 to 217.

EXAMPLE 6 2-chloro-1 1-hydroxy-S-methylmorphanthridin-G (5H) -oneDissolve 10 parts of 2-chloro-5-methylmorphanthridine- 6,l1(5H)-dione(title compound of Example 3) in 150 parts by volume of 95% ethanol; addsome chloroform thereto to clarify the obtained solution and heat theresultant clarified solution with 3.5 parts of sodium borohydride at 60(with stirring) for 20 minutes.

Thereafter cool the thus-treated material to room temperature, and addacid (preferably acetic acid) thereto in small portions until a clearsolution results. Concentrate the thus-obtained clear solution to halfits volume. Add 2 N sodium hydroxide (aq.) solution to the resultingconcentrate until it is slightly alkaline; then add water thereto toprecipitate the reaction product. Collect the precipitate, water-washand dry to obtain title compound, M.P. 195 to 198.

Extraction can alternatively be employed, but precipitation is fasterand is preferred.

EXAMPLE 7 2,11-dichloro--methylmorphanthridin-6(5H)-one Dissolve 8.5parts of 2-chloro-11-hydroxy-5-methylmorphanthridin-6(5H)-one (titlecompound of Example 6) in 120 parts by volume of thionyl chloride.Reflux the obtained solution for 3 hours. Then evaporate excess thionylchloride (add 60 parts by volume of benzene to the refluxed material andevaporate the resultant to dryness; add 60 parts by volume of benzene tothe residue and evaporate the resultant to dryness to remove all thionylchloride) from the refluxed material. When all of the thionyl chloridehas been removed, crystallize the residue from methylene chloride toobtain the title compound, M.P. 188 to 190.

For removal of the excess thionyl chloride other inert solvents, such aschloroform and toluene, can be used in place of benzene.

1 0 EXAMPLE 8 1-(5-chloro-2-methylaminophenyl)isoindo1in-3-one Dissolve5 parts of 2,11 dichloro 5 methylmorphanthridin-6(5H)-one (titlecompound of Example 7) in parts by volume of dry liquid ammonia, andheat the resulting solution for 16 hours at 100 in an autoclave.Evaporate the ammonia from. the autoclaved material, dissolve theresulting residue in 100 parts by volume of hot chloroform (containingsome ethanol), wash the obtained solution with Water, dry the washedsolution over sodium sulfate and then concentrate the dried material to10 parts by volume of solvent. Crystallize, filter off crystals andrecrystallize from chloroform/ethanol to obtain title compound, M.P. 225to 227.

EXAMPLE 9 Z-amino- 1- (5 0-chloro-Z-methylaminophenyl isoindolin-3-one &

Reflux 5.8 parts of 2,11 dichloro 5 methylmorphanthridin-6-one (titlecompound of Example 7) With 60 parts by volume of anhydrous hydrazinefor one hour. Pour the refluxed material into water, extract theresultant with methylene chloride, wash the organic phase first withWater and then with saturated (aq.) sodium chloride solution and thendry the thus-washed organic phase over sodium sulfate before evaporatingsame in vacuo. Crystallize the thus-produced oily residue withdiethylether, and filter off the title compound; recrystzallize frommethylene chloride/diethylether to obtain title compound, M.P. 62 to 64.(The title compound crystallizes with 1 mole of di ethylether as crystalsolvent.)

EXAMPLE 10 1-(5-chloro-2-methylaminophenyl)isoindolin-3 -one EXAMPLE 11-chloro-2'-methylaminobenzophenone- 2-carboxylic acid CH C1- Mix partsof 2 chloro-S-methylmorphanthridine- 6,1l(5H)-dione (title compound ofExample 3) with 175 parts by volume of 2 N (aq.) sodium hydroxidesolution and heat the resultant for minutes on a steam-bath. Cool theresulting clear solution to room temperature to precipitate the sodiumsalt of the title compound.

Add to the precipitate 150 parts by volume of water and then (understirring) 150 parts by volume of 2 -N (aq.) hydrochloric acid. Filterand water-wash the fine crystals which are thus formed. Dry the washedcrystals and recrystallize same from chloroform/ methanol to obtaintitle compound, M.P. 226 to 230.

EXAMPLE 12 1- chloro-2-methylaminophenyl -isoindolin-3 -one Mix 12 partsof 5'-chloro-2-methyl aminobenzophenone-Z-carboxylic acid (titlecompound of Example 11) with parts by volume of absolute ethanol.Saturate the obtained mixture (under cooling) with ammonia before addingthereto 3 parts of Raney-Nickel and hydrogenating for several hours atto under 2200 p.s.i.g. pressure. Cool the hydrogenated material to roomtemperature, evaporate solvent therefrom and crystallize the resultingresidue from chloroform to obtain title compound, M.P. 225 to 227.

EXAMPLE 13 1-(5-chloro-2-methylaminophenyl)isoindoline Dissolve 20 partsof 1 (5 chloro 2 methylaminophenyl)isoindolin-3-one (title compound ofExample 5) in 200 parts by volume of 1/1 water/ concentrated sulfuricacid. Cool the obtained solution to room temperature and add thereto 200parts by volume of water. Place the thus-diluted solution in a beakerwhich is equipped with a lead sheet electrode (200 square unitssurface). Submerge a porous cup (filled with sulfuric acid of the sameconcentration and equipped With a lead sheet electrode of the samesurface) into said diluted solution,

and connect the first electrode to the negative terminal and the secondelectrode to the positive terminal of a heavy duty 12-vo1t battery. Stirthe solution in the cathode chamber intensively and lectrolyze for 15hours at from 10 to 25.

Thereafter, remove the porous cup, and neutralize the sulfuric acid inthe beaker with 50% (aq.) sodium hydroxide solution (under cooling).Filter off precipitated crystals to obtain title compound, M.P. 133 to135.

Replacing the title compound of Example 5 with an equivalent of1-(2-methylaminophenyl)isoindolin-3-one results in the preparation, inthe same manner, of 1-(2- inethylaminophenyl)isoindoline, M.P. 99 to101.

EXAMPLE 14 1- 5-chloro-2methylaminophenyl) isoindolin- 2-acetic acidethyl ester EXAMPLE 152-chloro-5-methyl-9,13b-dihydro-5H-isoindolo[2,1-d] [1.4]benzodiazepin-6 (7H) -one N-CHa (raccmate) Dissolve the title compound(final residue) of Example 14 in parts by volume of glacial acetic acid.Heat the thus-obtained solution to boiling, and slowly distill therefromabout half of the acid. Then evaporate the remainder to dryness invacuo. Dissolve the residue in methylene chloride and introduce hydrogenchloride gas into the thus-prepared methylene chloride solution. Adddiethylether to this solution to precipitate the hydrochloride, M.P. 263to 266, of the title compound. On liberation from the acid addition saltby standard procedures, the free base, M.P. 171 to 173, is obtained.

Replacing the title compound of Example 14 with an equivalent of1-(Z-methylaminophenyl)isoindolin-Z-acetic acid ethyl ester results inthe preparation, in similar manner, of5-methyl-9,13b-dihydro-5H-isoindolo[2,1-d] [1,4]-benzodiazepin-6(7H)-one hydrochloride, M.P. 255 to 257.

EXAMPLE l6 Enantiomers of 1-(5-chloro-2-methylaminophenyl)- isoindolineAdd 6 parts of D-tartaric acid in 75 parts by volume of ethanol to asolution of 10.3 parts of (i)-1-(5-chloro- 75Z-methylaminophenyl)isoindoline (title compound of Example 13) in 120parts by volume of ethanol and 60 parts by volume of methylene chloride.Concentrate the resulting mixture to crystalize out the tartrate of the(+)-base, the tartrate of the base remaining in solution. Filter off thethus-crystallized precipitate and free the base therefrom bydistributing said precipitate between methylene chloride and diluteaqueous sodium hydroxide solution. Dry the organic phase, and thenevaporate the methylene chloride from same in vacuo. Crystallize theresidual crude base from methylene chloride/ethanol to obtain(+)-1-(5-chloro-2-methylaminophenyl)isoindoline, M.P. 100 to 102, [a]+44 (c.=1.5, chloroform).

Evaporate the filtrate of the tartrate of the (+)-base to dryness invacuo and distribute the residue between methylene chloride and dilute(aq.) sodium hydroxide solution. Dry the organic phase, and evaporatethe solvent from same in vacuo. Transfer the thus-obtained residue,consisting primarily of the (--)base, (in the same manner as describedabove) to the crystalline L-tartrate by addition thereto of L-tartaricacid. The free base (-)-1- (-chloro-2-methylaminophenyl)isoindoline,M.P. 100 to 101, [cc] =43.6 (c.=1.5, chloroform), is thus prepared fromthe tartrate in the same Way as described above for the free )-base.

EXAMPLE 17 Enantiomers of 1-(5-chloro-2-methylaminophenyl)isoindolin-Z-acetic acid ethyl ester Reflux 3 parts of(+)-1-(S-chloroZ-methylaminophenyl)isoindoline, 2 parts of ethylbromoacetate and 2 parts of triethylamine in 75 parts by volume ofethanol for 2 hours. Evaporate the thus-refluxed material to dryness.Dissolve the obtained residue in benzene. Wash the benzene (organic)phase sequentially With water, 2 N (aq.) sodium hydroxide solution, 1 N(aq.) hydrochloric acid and with saturated (aq.) sodium chloridesolution. Then evaporate the thus-washed organic phase to dryness invacuo to obtain (+)-1-(5-chloro-2-methylaminophenyl)isoindolin-Z-aceticacid ethyl ester as residue.

Replacing the -1- 5-chloro-2-methylaminophenyl) isoindoline with anequivalent of (-)-l-(5-chloro-2- methylaminophenyl)isoindoline resultsin the preparation in similar manner, of()-1-(5-chloro-2-methylaminophenyl)isoindolin-Z-acetic acid ethyl ester.

EXAMPLE 18 (-)-2-chloro-5-methyl-9,13b-dihydro-5H-isoindolo [2,1-d][1,4]'benzodiazepin-6 (7H) -one Dissolve the 1- 5-chloro-2-methylaminophenyl) isoindolin-Z-acetic acid ethyl esterresidue from Example 17 in 30 parts by volume of glacial acetic acid.Boil the thus-obtained solution for 2 hours while some of the aceticacid distills oif. Then evaporate therefrom all remaining acetic acid.Dissolve the thus-obtained residue in methylene chloride, and Wash theorganic phase with dilute (aq.) sodium hydroxide solution and withWater. Evaporate the thus-Washed organic (methylene chloride) phase todryness and crystallize the residue from diethylether. Filter offcrystals of the title compound, M.P. 173 to 175, [u] =-.207 (6:0.5,ethanol).

Replacing the (+)-1-(5-chloro-Z-methylaminophenyl)- isoindolin-Z-aceticacid ethyl ester with an equivalent of the-1-(5-chloro-2-methylaminophenyl) isoindolin-2- acetic acid ethyl esterresults in the preparation, in similar manner, of(+)-2-chloro-5-methyl-9,13'b-dihydro-5H- isoindolo[2,l d][1,4]benzodiazepin 6(7H) one, [fl]54 =+210 (CZOXS, 6131131101).

The invention is readily understood from the foregoing description.Various changes may be made in procedures and in the intermediateswithout departing from the spirit and scope of the invention orsacrificing its material advantages. The examples presented herein aremerely illustrative embodiments.

What is claimed is:

1. A compound of the formula wherein each of rings A and B is,independently, a member selected from the group consisting of anunsubstituted benzene ring and a benzene ring substituted by at leastone halogen selected from the group consisting of a chlorine atom, afluorine atom and a bromine atom; and R is a member selected from thegroup consisting of methyl and ethyl. 2. The compound according to claim1 which is 1- amino 1 (5-chloro-2-methylaminophenyl)isoindolin-3- one.

3. The compound according to claim 1 which is 1- amino 1(2-methylaminophenyl)isoindolin-3-one.

4. A compound of the formula R" is a member selected from the groupconsisting of a hydrogen atom and -NH 5. The compound according to claim4 which is 1-(5- chloro-2-methylaminophenyl)isoindolin-S-one.

6. The compound according to claim 4 which is 1-(2- methylaminophenyl)isoindolin-3 -one.

7. The compound according to claim 4 which is 2-amino-1-(5-chloro-2-methylaminophenyl)isoindolin 3 one.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner J. A. NARCAVAGE, Assistant Examiner

